Chronic obstructive pulmonary disease (COPD), a disease caused by the chronic inhalation of tobacco cigarette smoke, is currently the fourth leading cause of death in the US. COPD is characterized by a progressive decline in lung function that has recently been linked to the development of lung cancer. Several recent studies have demonstrated that lung cancer incidence correlates with declining FEV1, a measurement of disease severity. The interrelationship between COPD and lung cancer is poorly understood. A role for cigarette smoke in carcinogenesis via epithelial cell damage and DMA adduct formation is well documented. However, these data suggest that the presence of COPD predisposes one to the development of lung cancer independent of smoking history. One aspect of COPD that may influence lung tumorigenesis is inflammation. Emphysema, a major component of COPD, is characterized by an inflammatory cell infiltrate composed of macrophages, neutrophils, and lymphocytes, and by the presence of proteinases in excess of their inhibitors. The impact that these cells and proteinases have on important aspects of lung tumorigenesis such as angiogenesis, cellular proliferation, tissue invasion, and metastasis, remains poorly understood. We hypothesize that the inflammatory cell infiltrate generated by cigarette smoke exposure plays a pro-tumor role in lung tumorigenesis. To test this concept, we propose to study the impact of emphysema-related inflammatory cells and proteinases on lung tumorigenesis in vivo using a activating K-ras mutant murine model of lung cancer. The applicant intends to use the proposed period of support and training to obtain the necessary experience, proficiency, and guidance to develop an independent research career. The area of focus now and in the future will be to investigate the inflammatory cells and proteinases common to both COPD and lung cancer, in lung tumorigenesis. Lay Abstract. Chronic obstructive pulmonary disease (COPD) has recently been linked to the development of lung cancer. Taken together, these two diseases account for greater than 350,000 deaths annually in the US. The means by which COPD predisposes an individual to the development of lung cancer is not known. We propose to study this relationship by examining the effect of cigarette smoke-induced emphysema and its associated inflammation on lung cancer progression using a mouse model of lung cancer. (End of Abstract)